Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease

Abstract CYP8B1 has been identified as a potential target for the treatment of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). CYP8B1 enzyme inhibitor 1 was discovered from a high-throughput screen of our compound collection; however, its poor metabolic stability prevented further in vivo evaluation. Leveraging structure-based drug design, metabolite identification and metabolic stability-guided DMPK optimization, and library synthesis to rapidly expand SAR, we identified compound 9 with substantially improved DMPK properties. Compound 9 showed robust in vivo CYP8B1 inhibition in mice and provided the foundation for further optimization of this class of CYP8B1 inhibitors.